Meiosis I maturation arrest accounts for a significant fraction of idiopathic male infertility cases in humans. We propose to investigate the causes and molecular mechanism of meiosis I maturation arrest using Drosophila and mouse animal models. Five Drosophila genes, spermatocyte arrest, cannonball, always early, meiosis I arrest, and blockout, are required for progression of male meiosis and onset of spermatid differentiation. Mutations in these genes cause defects also characteristic of human meiosis I maturation arrest; early stages of spermatogenesis appear normal, spermatocytes with partially condensed chromosomes accumulate, and testes lack post-meiotic spermatids. This striking phenotypic similarity strongly suggests a crucial control point at the onset of meiotic division in males that is conserved from flies to man. We propose to identify the molecular nature and probe the mode of action of three of these genes and test the hypothesis that mammalian homologues of the Drosophila genes serve an analogous function in meiosis I maturation arrest. Identification of cause(s) of meiosis I maturation arrest could lead to preventive regimens, while understanding of its molecular mechanism could guide development of therapeutic interventions. To elucidate how the spermatocyte arrest type genes act to ensure normal spermatogenesis, we will determine the molecular nature of the Drosophila gene products, isolate mouse homologues, and determine in what cell types and stages of spermatogenesis the genes are expressed and the sub-cellular location of their protein products. To test if mutations in these genes cause meiosis I maturation arrest in mammals we will construct and phenotypically analyze mouse knockout mutations. If homozygous mutant mice also display meiosis I arrest, then the causes and mechanism of meiosis I maturation arrest are probably conserved from Drosophila to man and the basis mechanisms we elucidate in Drosophila should apply to understanding the condition in man. We will determine whether progression through male meiosis requires a permissive signal from somatic testis cells by germ cell transplantation and assess the role of the spermatocyte arrest type genes in the signaling process. Finally, we will use the power of genetic analysis in Drosophila to identify additional genes required for arrest at the meiosis I control point by screening for suppressors of the Drosophila mutants.